chr4-39205726-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_025132.4(WDR19):c.880G>A(p.Gly294Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000375 in 1,598,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

WDR19
NM_025132.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.55

Publications

2 publications found

Variant links:

Genes affected

WDR19 (HGNC:18340): (WD repeat domain 19) The protein encoded by this gene is a member of the WD (tryptophan-aspartic acid) repeat family, which is a large family of structurally-related proteins known to participate in a wide range of cellular processes. Each WD repeat typically contains about 40 amino acids that are usually bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. This protein contains six WD repeats, three transmembrane domains, and a clathrin heavy-chain repeat. Mutations in this gene have been described in individuals with a wide range of disorders affecting function of the cilium. These disorders are known as ciliopathies, and include Jeune syndrome, Sensenbrenner syndromes, Senior-Loken syndrome, combined or isolated nephronophthisis (NPHP), and retinitis pigmentosa (RP). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

WDR19 Gene-Disease associations (from GenCC):

asphyxiating thoracic dystrophy 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cranioectodermal dysplasia 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
nephronophthisis 13
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Senior-Loken syndrome 8
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cranioectodermal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nephronophthisis 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

WDR19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 4-39205726-G-A is Pathogenic according to our data. Variant chr4-39205726-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR19	NM_025132.4	MANE Select	c.880G>A	p.Gly294Arg	missense	Exon 9 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.400G>A	p.Gly134Arg	missense	Exon 8 of 36	NP_001304853.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR19	ENST00000399820.8	TSL:1 MANE Select	c.880G>A	p.Gly294Arg	missense	Exon 9 of 37	ENSP00000382717.3
WDR19	ENST00000503697.5	TSL:1	n.*348G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000423706.1
WDR19	ENST00000503697.5	TSL:1	n.*348G>A		3_prime_UTR	Exon 7 of 9	ENSP00000423706.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000268

AC:

AN:

224124

AF XY:

0.0000249

show subpopulations

Gnomad AFR exome

AF:

0.0000707

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000502

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000360

AC:

AN:

1446332

Hom.:

Cov.:

AF XY:

0.0000251

AC XY:

AN XY:

717850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33306

American (AMR)

AF:

0.00

AC:

AN:

42162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25756

East Asian (EAS)

AF:

0.00

AC:

AN:

39390

South Asian (SAS)

AF:

0.00

AC:

AN:

83602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000453

AC:

AN:

1103894

Other (OTH)

AF:

0.0000334

AC:

AN:

59866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Jeune thoracic dystrophy

Pathogenic:2

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Asphyxiating thoracic dystrophy 5;C3280612:Nephronophthisis 13;C3280616:Cranioectodermal dysplasia 4;C4225376:Senior-Loken syndrome 8;C5676980:Spermatogenic failure 72

Pathogenic:1

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8

Pathogenic:1

Dec 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WDR19 protein function. ClinVar contains an entry for this variant (Variation ID: 446635). This missense change has been observed in individual(s) with clinical features of WDR19-related conditions (PMID: 26275793, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs377160857, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the WDR19 protein (p.Gly294Arg).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

9.5

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

Sift4G

Benign

0.078

Polyphen

1.0

Vest4

0.98

MutPred

0.65

Gain of sheet (P = 0.0477)

MVP

0.97

MPC

0.76

ClinPred

0.99

GERP RS

5.5

Varity_R

0.89

gMVP

0.94

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over